Humanity is facing an epidemic of interrelated obesity-associated disorders including insulin-resistance, hyperlipidemia, hepatic steatosis and hypertension that are collectively referred to as metabolic syndrome. Pioneering work by Jeff Gordon and colleagues have demonstrated that a central component of metabolic syndrome, namely obesity, is influenced by the ability of an individual's intestinal microbiota to mediate energy harvest from ingested food. Our work, which this competitive renewal application seeks to sustain, has developed the hypothesis that gut microbiota plays a pivotal role in numerous aspects of metabolic syndrome primarily via driving low-grade inflammation. This hypothesis builds upon the inflammatory explanation for insulin resistance that seeks to explain the causal link between obesity and type 2 diabetes. However, our hypothesis holds that inflammation is not purely a consequence of obesity but, rather, alterations in gut microbiota drive low-grade inflammation that promote adiposity via driving lipogenesis and interfering with metabolic receptor signaling (e.g. insulin and leptin receptors). Work performed under this grant demonstrates that such alterations in microbiota composition can originate from a variety of underlying causes including an innate immune deficiency, timely presence of pathobiont bacteria, or select food additives. That altered microbiota are not merely a marker of inflammation but drive inflammation and metabolic syndrome in these mouse models is supported by our demonstration that transplanting them recapitulates the low-grade inflammation/metabolic syndrome phenotype in the recipients. While the specific microbial species whose abundance is altered differs depending upon mouse strain, vivarium, and underlying cause of low-grade inflammation, this project has revealed general functional features of microbiotas associated with models of metabolic syndrome. Specifically, we've observed that microbiotas associated with metabolic syndrome, in mice, express high levels of activators of the innate immune system and, moreover, penetrate the inner mucus layer thus encroaching upon intestinal epithelial cells. Our long-term goal is to define the molecular events that result in such alterations and develop approaches to restore a more beneficial host-microbiota relationship thus allowing design of modalities to ameliorate the metabolic syndrome epidemic in humans. Herein, we propose to advance toward this goal.